Nuclear receptors constitutive androstane receptor and pregnane X receptor activate a drug-responsive enhancer of the murine 5-aminolevulinic acid synthase gene

被引:58
作者
Fraser, DJ [1 ]
Zumsteg, A [1 ]
Meyer, UA [1 ]
机构
[1] Univ Basel, Bioctr, Dept Pharmacol Neurobiol, Div Pharmacol Neurobiol, CH-4056 Basel, Switzerland
关键词
D O I
10.1074/jbc.M306148200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Nuclear receptors have been implicated in the transcriptional regulation of expression of a growing number of genes, including cytochromes P450 and 5-aminolevulinate synthase (ALAS1), the first and rate-limiting enzyme in the heme biosynthesis pathway. Although drugs that induce cytochromes P450 also induce ALAS1, the regulatory mechanisms governing these pathways have not been fully elucidated. We have identified a drug-responsive enhancer in the murine ALAS1 gene. This sequence mediates transcriptional activation by a wide range of compounds including typical cytochrome P450 pan-inducers phenobarbital and metyrapone, as well as specific activators of the pregnane X receptor and the constitutive androstane receptor. ALAS1 drug-responsive enhancer sequences were identified by transient transfection of reporter gene constructs in the drug-responsive leghorn male hepatoma cell line. Using the NUBIScan algorithm, DR4 nuclear receptor binding sites were identified within the elements and their roles in mediating transcriptional activation of ALAS1 were confirmed by site-directed mutagenesis. Electrophoretic mobility shift assays demonstrate clear interactions of mouse pregnane X receptor and constitutive androstane receptor on the ADRES. Transactivation assays in CV-1 cells implicate the nuclear receptors as major contributors to transcriptional activation of ALAS1. Moreover, in vivo studies in knock-out animals confirm the induction of ALAS1 is mediated at least in part by nuclear receptors. These studies are the first to explain drug induction via drug response elements for mammalian ALAS1.
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收藏
页码:39392 / 39401
页数:10
相关论文
共 37 条
  • [1] Regulation of P450 genes by liver-enriched transcription factors and nuclear receptors
    Akiyama, TE
    Gonzalez, FJ
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 2003, 1619 (03): : 223 - 234
  • [2] Anderson K. E., 2001, METABOLIC BASIS INHE
  • [3] Transcriptional activation of cytochrome P450CYP2C45 by drugs is mediated by the chicken xenobiotic receptor (CXR) interacting with a phenobarbital response enhancer unit
    Baader, M
    Gnerre, C
    Stegeman, JJ
    Meyer, UA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (18) : 15647 - 15653
  • [4] Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction
    Bertilsson, G
    Heidrich, J
    Svensson, K
    Åsman, M
    Jendeberg, L
    Sydow-Bäckman, M
    Ohlsson, R
    Postlind, H
    Blomquist, P
    Berkenstam, A
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (21) : 12208 - 12213
  • [5] SXR, a novel steroid and xenobiotic-sensing nuclear receptor
    Blumberg, B
    Sabbagh, W
    Juguilon, H
    Bolado, J
    van Meter, CM
    Ono, ES
    Evans, RM
    [J]. GENES & DEVELOPMENT, 1998, 12 (20) : 3195 - 3205
  • [6] Effects of modulators of protein phosphorylation on heme metabolism in human hepatic cells:: Induction of δ-aminolevulinic synthase mRNA and protein by okadaic acid
    Cable, EE
    Kuhn, BR
    Isom, HC
    [J]. DNA AND CELL BIOLOGY, 2002, 21 (04) : 323 - 332
  • [7] Regulation of heme metabolism in rat hepatocytes and hepatocyte cell lines:: δ-aminolevulinic acid synthase and heme oxygenase are regulated by different heme-dependent mechanisms
    Cable, EE
    Miller, TG
    Isom, HC
    [J]. ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2000, 384 (02) : 280 - 295
  • [8] Regulation of human CYP2C9 by the constitutive androstane receptor:: Discovery of a new distal binding site
    Ferguson, SS
    Lecluyse, EL
    Negishi, M
    Goldstein, JA
    [J]. MOLECULAR PHARMACOLOGY, 2002, 62 (03) : 737 - 746
  • [9] Drugs mediate the transcriptional activation of the 5-aminolevulinic acid synthase (ALAS1) gene via the chicken xenobiotic-sensing nuclear receptor (CXR)
    Fraser, DJ
    Podvinec, M
    Kaufmann, MR
    Meyer, UA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (38) : 34717 - 34726
  • [10] Transcriptional regulation of CYP2C9 gene -: Role of glucocorticoid receptor and constitutive androstane receptor
    Gerbal-Chaloin, S
    Daujat, M
    Pascussi, JM
    Pichard-Garcia, L
    Vilarem, MJ
    Maurel, P
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (01) : 209 - 217